Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy

Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B. Haack, Salim Khiati, Anne Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A. Aleck, Lorenzo D. Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N'Guyen, José Antonio Mora-Lorca, Birgit AssmannStine Christ, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Emmanuelle Génin, Dominique Campion, Jean François Dartigues, Jean François Deleuze, Jean Charles Lambert, Richard Redon, Thomas Ludwig, Benjamin Grenier-Boley, Sébastien Letort, Pierre Lindenbaum, Vincent Meyer, Olivier Quenez, Christian Dina, Céline Bellenguez, Camille Charbonnier -Le Clézio, Joanna Giemza, Stéphanie Chatel, Claude Férec, Hervé Le Marec, Luc Letenneur, Gaël Nicolas, Karen Rouault, Delphine Bacq, Anne Boland, Doris Lechner, Antonio Miranda-Vizuete, Georg F. Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.

Original languageEnglish
Pages (from-to)695-703
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number3
DOIs
StatePublished - 1 Sep 2016

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